Benzonaphthyridines as bronchial therapeutics

ABSTRACT

Compounds of formula (I) in which R1, R2, R3 and R4 have the meanings indicated in the description, are novel active bronchial therapeutics

This application is the national phase of PCT/EP97/06096, filed Nov. 5,1997, published as WO 98/21208 on May 22, 1998.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to novel 6-phenylbenzonaphthyridines which areused in the pharmaceutical industry for the production of medicaments.

KNOWN TECHNICAL BACKGROUND

DE-A 21 23 328 and U.S. Pat. No. 3,899,494 describe substitutedbenzonaphthyridines which are distinguished by marked inhibition ofblood platelet aggregation. EP 247 971 and WO 91/17991 disclose6-phenyl-benzonaphthyridines for the treatment of inflammatory airwaydisorders.

DESCRIPTION OF THE INVENTION

It has now been found that the following compounds of the formula Iwhich are described in greater detail and differ from the compounds ofEP 247 971 or WO91/17991, in particular, by the substitution on the6-phenyl ring, have surprising and particularly advantageous properties.

The invention thus relates to compounds of the formula I ##STR2## inwhich R1 is 1-4C-alkyl,

R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or1-4C-alkoxy which is completely or predominantly substituted byfluorine,

R3 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or1-4C-alkoxy which is completely or predominantly substituted byfluorine,

or in which

R2 and R3 together are a 1-2C-alkylenedioxy group,

R4 is a phenyl radical which is substituted by R5 and R6, where

R5 is hydrogen, hydroxyl, halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

R6 is CO--R7 or CO--R8, where

R7 is hydroxyl, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxyand

R8 is N(R81)R82, where R81 and R82 independently of one another arehydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or whereR81 and R82, together and including the nitrogen atom to which both arebonded, are a 1-pyrrolidinyl, 1-piperidyl, 1-hexahydroazepinyl or4-morpholinyl radical,

and to the salts of these compounds.

1-4C-Alkyl represents a straight-chain or branched alkyl radical having1 to 4 carbon atoms. Examples which may be mentioned are the butyl,isobutyl, sec-butyl, tert-butyl, propyl, isopropyl and, preferably, theethyl and methyl radicals.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and, preferably, the ethoxyand methoxy radicals.

3-7C-Cycloalkoxy represents, for example, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of whichcyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-Cycloalkylmethoxy represents, for example, cyclopropylmethoxy,cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy andcycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy andcyclopentylmethoxy are preferred.

As 1-4C-Alkoxy which is completely or predominantly substituted byfluorine, the 2,2,3,3,3-pentafluoropropoxy, the perfluoroethoxy, the1,1,2,2-tetrafluoroethoxy, the 1,2,2-trifluoroethoxy, thetrifluoromethoxy, in particular the 2,2,2-trifluoroethoxy, andpreferably the difluoromethoxy radicals, for example, may be mentioned.

1-2C-Alkylenedioxy represents, for example, the methylenedioxy (--O--CH₂--O--) or the ethylenedioxy radical (--O--CH₂ --CH₂ --O--).

Halogen within the meaning of the invention is fluorine, chlorine orbromine.

1-8C-Alkoxy represents radicals, which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 8 carbonatoms. Examples which may be mentioned are the octyloxy, heptyloxy,hexyloxy, pentyloxy, methylbutoxy, ethylpropoxy, butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy or, preferably, the isopropoxy, ethoxyor methoxy radical.

1-7C-Alkyl represents straight-chain or branched alkyl radicals having 1to 7 carbon atoms. Examples which may be mentioned are the heptyl,isoheptyl (5-methylhexyl), hexyl, isohexyl (4-methylpentyl), neohexyl(3,3-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl(2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl,isopropyl, ethyl or methyl radical.

3-7C-Cycloalkyl represents the cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl radical.

3-7C-Cycloalkylmethyl represents a methyl radical which is substitutedby one of the abovementioned 3-7C-cycloalkyl radicals. Examples whichmay be mentioned are the cycloalkylmethyl radicals cyclopropylmethyl,cyclobutylmethyl and cyclopentylmethyl.

Suitable salts of compounds of the formula I--depending onsubstitution--are all acid addition salts or all salts with bases. Thepharmacologically tolerable salts of the inorganic and organic acids andbases customarily used in pharmacy may be particularly mentioned. Thosesuitable are, on the one hand, water-soluble and water-insoluble acidaddition salts with acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, aceticacid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxylbenzoyl)benzoic acid, butyric acid, sutfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 3-hydroxyl-2-naphthoic acid, where theacids are employed in salt preparation--depending on whether a mono- orpolybasic acid is concerned and depending on which salt is desired--inan equimolar quantitative ratio or one differing therefrom.

On the other hand--for example in the case of carboxylsubstitution--salts with bases are also suitable. Examples of salts withbases which may be mentioned are alkali metal (lithium, sodium,potassium) or calcium, aluminum, magnesium, titanium, ammonium,meglumine or guanidinium salts, where here too the bases are employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts which can be obtained first, forexample, as process products in the preparation of the compoundsaccording to the invention on an industrial scale, are converted intopharmacologically tolerable salts by methods known to the person skilledin the art.

According to expert's knowledge the compounds of the invention as wellas their salts may contain, e.g. when isolated in crystalline form,varying amounts of solvents. Included within the scope of the inventionare therefore all solvates and in particular all hydrates of thecompounds of formula I as well as all solvates and in particular allhydrates of the salts of the compounds of formula I.

Compounds of the formula I to be emphasized are those in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or1-2C-alkoxy which is completely or predominantly substituted byfluorine,

R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or1-2C-alkoxy which is completely or predominantly substituted byfluorine,

R4 is a phenyl radical which is substituted by R5 and R6, where

R5 is hydrogen, hydroxyl, halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

R6 is CO--R7 or CO--R8, where

R7 is hydroxyl, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxyand

R8 is N(R81)R82, where R81 and R82 independently of one another arehydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or whereR81 and R82, together and including the nitrogen atom to which both arebonded, are a 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,

and the salts of these compounds.

One embodiment of the compounds of the formula I to be emphasized arethose compounds in which

R1 is 1-4C-alkyl,

R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or1-2C-alkoxy which is completely or predominantly substituted byfluorine,

R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or1-2C-alkoxy which is completely or predominantly substituted byfluorine,

R4 is a phenyl radical which is substituted by R5 and R6, where

R5 is hydrogen, hydroxyl, halogen, nitro, 1-4C-alkyl, trifluoromethyl or1-4C-alkoxy,

R6 is CO--R7 or CO--R8, where

R7 is hydroxyl, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxyand

R8 is N(R81)R82, where R81 and R82 independently of one another arehydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or whereR81 and R82, together and including the nitrogen atom to which both arebonded, are a 1-piperidyl or 1-hexahydroazepinyl radical,

and the salts of these compounds.

Compounds of the formula I particularly to be emphasized are those inwhich

R1 is methyl,

R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 1-2C-alkoxy which is completelyor predominantly substituted by fluorine,

R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 1-2C-alkoxy which is completelyor predominantly substituted by fluorine,

R4 is a phenyl radical which is substituted by R5 and R6, where

R5 is hydrogen, hydroxyl, 1-4C-alkyl or 1-4C-alkoxy,

R6 is CO--R7 or CO--R8, where

R7 is hydroxyl, 1-8C-alkoxy or 3-7C-cycloalkoxy and

R8 is N(R81)R82, where R81 and R82 independently of one another arehydrogen, 1-7C-alkyl or 3-7C-cycloalkyl, or where R81 and R82, togetherand including the nitrogen atom to which both are bonded, are a1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,

and the salts of these compounds.

One embodiment of the compounds of the formula I particularly to beemphasized are those compounds in which

R1 is methyl,

R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 1-2C-alkoxy which is completelyor predominantly substituted by fluorine,

R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 1-2C-alkoxy which is completelyor predominantly substituted by fluorine,

R4 is a phenyl radical which is substituted by R5 and R6, where

R5 is hydrogen, hydroxyl, 1-4C-alkyl or i4C-alkoxy,

R6 is CO--R7 or CO--R8, where

R7 is hydroxyl, 1-8C-alkoxy or 3-7C-cycloalkoxy and

R8 is N(R81)R82, where R81 and R82 independently of one another arehydrogen, 1-7C-alkyl or 3-7C-cycloalkyl,

and the salts of these compounds.

Preferred compounds of the formula I are those in which

R1 is methyl,

R2 is methoxy or ethoxy,

R3 is methoxy or ethoxy,

R4 is a phenyl radical which is substituted by R5 and R6, where

R5 is hydrogen,

R6 is CO--R7 or CO--R8, where

R7 is hydroxyl or 1-8C-alkoxy and

R8 is N(R81)R82, where R81 and R82 independently of one another arehydrogen or 1-4C-alkyl or 5-7C-cycloalkyl, or where R81 and R82,together and including the nitrogen atom to which both are bonded, are a1-piperidyl, 1-hexahydroazepinyl or 4morpholinyl radical,

and the salts of these compounds.

One embodiment of the preferred compounds of the formula I are thosecompounds in which

R1 is methyl,

R2 is methoxy or ethoxy,

R3 is methoxy or ethoxy,

R4 is a phenyl radical which is substituted by R5 and R6,, where

R5 is hydrogen,

R6 is CO--R7 or CO--R8, where

R7 is hydroxyl or 1-8C-alkoxy and

R8 is N(R81)R82, where R81 and R82 independently of one another arehydrogen or 1-4C-alkyl,

and the salts of these compounds.

Particularly preferred compounds of the formula I are those in which

R1 is methyl,

R2 is ethoxy,

R3 is methoxy or ethoxy,

R4 is a phenyl radical which is substituted by R5 and R6, where

R5 is hydrogen,

R6 is CO--R7 or CO--R8, where

R7 is 1-4C-alkoxy and

R8 is N(R81)R82, where R81 and R82 independently of one another are1-4C-alkyl or -5-7C-cycloalkyl, or where R81 and R82, together andincluding the nitrogen atom to which both are bonded, are a 1-piperidylor 1-hexahydroazepinyl radical,

and the salts of these compounds.

The compounds of the formula I are chiral compounds having chiralcenters in positions 4a and 10b ##STR3##

The invention therefore includes all conceivable pure diastereomers andpure enantiomers and mixtures thereof in any mixing ratio, including theracemates. Preferred are those compounds of the formula I in which thehydrogen atoms in positions 4a and 10b are in the cis position relativeto one another. The pure cis enantiomers and their mixtures in anymixing ratio and including the racemates are particularly preferredhere.

Particularly preferred in this connection are those compounds of theformula I which in positions 4a and 10b have the same absoluteconfiguration as the compound(-)-cis-4-amino-3-(3,4-dimethoxyphenyl)-1-methylpiperidinedihydrochloride having the optical rotation [α]²² _(D) -57.1° (c=1,methanol) which can be employed as a starting material and is describedin DE 42 17 401.

Especially to be emphasized are those compounds of formula I which canbe prepared starting from the starting compounds(-)-cis-4-Amino-3-(3,4-diethoxyphenyl)-1-methylpiperidinedihydrochloride (example F) or(-)-cis-4-Amino-3-(3-ethoxy-4-methoxyphenyl)-1-methylpiperidinedihydrochloride (example O) and are selected from

cis-8,9-Diethoxy-6-(4-isopropoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine;

cis-8,9-Diethoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a-10b-hexahydrobenzo[c]-[1,6]naphthyridine;

cis-8,9-Diethoxy-6-(4-N-cyclohexyl-N-isopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;

cis-8,9-Diethoxy-6-(4-dibutylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine;

cis-8,9-Diethoxy-6-[4-(hexahydroazepin-1-yl-carbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;

cis-8,9-Diethoxy-6-[4-(piperidin-1-ylcarbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine;

cis-9-Ethoxy-8-methoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;

cis-9-Ethoxy-8-methoxy-6-(4-dibutylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridine;

cis-9-Ethoxy-8-methoxy-6-[4-(hexahydroazepin-1-yl-carbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;

cis-9-Ethoxy-8-methoxy-6-[4-(piperidin-1-yl-carbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine

and the salts of these compounds.

The enantiomers can be separated in a known manner (for example bypreparation and separation of corresponding diastereoisomeric compounds)or by stereoselective synthesis methods. Such separation processes andsynthesis methods are described, for example, in EP 247 971 and in DE4217 401.

The invention further relates to a process for the preparation of thecompounds of the formula I, in which R1, R2, R3 and R4 have the meaningsindicated above, and their salts. The process comprises subjectingcompounds of the formula II ##STR4## in which R1, R2, R3 and R4 have themeanings indicated above, to a cyclocondensation reaction and, ifdesired, then converting the compounds of the formula I obtained intotheir salts, or, if desired, then converting salts of the compounds ofthe formula I obtained into the free compounds.

If desired, compounds of the formula I obtained can be converted intofurther compounds of the formula I by derivatization. For example, thecorresponding acids can be obtained from compounds of the formula I inwhich R4 is a phenyl radical which is substituted by R5 and R6, and R6is an ester group, by acidic or alkaline hydrolysis, or thecorresponding amides can be prepared by reaction with amines of theformula HN(R81)R82, in which R81 and R82 have the meanings indicatedabove. The reactions are expediently carried out analogously to themethods known to the person skilled in the art, e.g. as described in thefollowing examples.

The cyclocondensation is carried out in a manner known per se to theperson skilled in the art according to Bischler-Napieralski (e.g. asdescribed in J. Chem. Soc., 1956, 4280-4282) in the presence of asuitable condensing agent, such as, for example, polyphosphoric acid,phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide,thionyl chloride or preferably phosphorus oxytrichloride, in a suitableinert solvent, e.g. in a chlorinated hydrocarbon such as chloroform, orin a cyclic hydrocarbon such as toluene or xylene, or another inertsolvent such as acetonitrile, or without a further solvent using anexcess of condensing agent, preferably at elevated temperature, inparticular at the boiling temperature of the solvent or condensing agentused.

Compounds of the formula II in which R1, R2, R3 and R4 have the meaningsindicated above are accessible from the corresponding compounds of theformula Ill ##STR5## in which R1, R2 and R3 have the meanings indicatedabove, by reaction with compounds of the formula R4--CO--X in which R4has the meaning indicated above and X is a suitable leaving group,preferably a chlorine atom. For example, the benzoylation is carried outas in the following examples according to the Einhorn process, theSchotten-Baumann variant or as described in J. Chem. Soc. (C), 1971,1805-1808.

The preparation of cis/trans racemate mixtures and of pure cis racematesof compounds of the formula III is described, for example, in U.S. Pat.No. 3,899,494, in DE-A 21 23 328 and in DE-A 16 95 782. Pure cisenantiomers of the compounds of the formula III can be obtained, forexample, by the processes as are disclosed in EP 0 247 971 and in DE 4217 401.

Compounds of the formula R4--CO--X are either known or can be preparedin a known manner.

The substances according to the invention are isolated and purified in amanner known per se, for example by distilling off the solvent in vacuoand recrystallizing the residue obtained from a suitable solvent orsubjecting it to one of the customary purification methods, such as, forexample, column chromatography on a suitable support material.

Salts are obtained by dissolving the free compound in a suitablesolvent, e.g. in a chlorinated hydrocarbon, such as methylene chlorideor chloroform, or a low molecular weight aliphatic alcohol (ethanol,isopropanol) which contains the desired acid or base, or to which thedesired acid or base is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted into thefree compounds, which can in turn be converted into salts, byalkalization or by acidification. In this manner, pharmacologicallyintolerable salts can be converted into pharmacologically tolerablesalts.

The following examples serve to illustrate the invention in greaterdetail without restricting it. Further compounds of the formula I, whosepreparation is not explicitly described, can also be prepared in ananalagous manner or in a manner familiar per se to the person skilled inthe art using customary process techniques.

In the examples, m.p. stands for melting point, h for hour(s), RT forroom temperature, EF for empirical formula, MW for molecular weight,calc. for calculated. The compounds mentioned in the examples and theirsalts are a preferred subject of the invention.

EXAMPLES FINAL PRODUCTS

1.(-)-cis-8,9-Dimethoxy-6-(4-methoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

2.31 g of (-)-cis-terephthalic acidN-[3-(3,4-dimethoxyphenyl)-1-methylpiperidin-4-yl]amide mono-methylester are heated to boiling under reflux for 4 h in 25 ml ofacetonitrile and 3 ml of phosphorus oxytrichloride. After distilling offthe excess phosphorus oxytrichloride, the residue is partitioned betweendichloromethane and saturated sodium hydrogencarbonate solution. Theorganic phase is washed with water, dried over sodium sulfate andconcentrated. The solid residue is purified by silica gelchromatography, the main product fraction is separated and this isconcentrated. The solid residue is dissolved in a little methanol, andthe solution is treated with one equivalent of aqueous HCl andconcentrated. The solid residue is recrystallized in methanol/diethylether. 1.76 g (70% of theory) of the title compound are obtained as a1.25-hydrochloride 0.5-hydrate having the m.p. 188-192° C. (unsharp,slow deliquescence).

EF: C₂₃ H₂₆ N₂ O₄ ×1.25HCl×0.5H₂ O; MW: 449.05

Elemental analysis: Calc.: C, 61.52; H, 6.34; Cl, 9.87; N, 6824. Found:C, 61.52; H, 6.19; Cl, 9.93; N, 623.

Optical rotation: [α]²⁰ _(D) -66° (c=1 , methanol).

Starting from the corresponding starting compounds described below, thefollowing title compounds are obtained analogously to Example 1:

2.(-)-cis-8,9-Dimethoxy-6-(3-methoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₃ H₂₆ N₂ O₄ ×1.1HCl×0.23H₂ O; MW: 438.69; m.p. from about 155° C.slow deliquescence; yield: 63% of theory

Elemental analysis: Calc.: C, 63.08; H, 6.32; Cl, 8.90; N, 6.40. Found:C, 63.13; H, 6.53; Cl, 8.81; N, 6.53.

Optical rotation: [α]²⁰ _(D) -90.8° (c=1, methanol).

3.(-)-cis-8,9-Dimethoxy-6-(4-isoropoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₅ H₃₀ N₂ O₄ ×1.15HCl×0.8H₂ O; MW: 478.79; m.p. 166-170° C.; yield:65% of theory;

Elemental analysis: Calc.: C, 62.84; H, 6.88; Cl, 8.53; N, 5.86. Found:C, 62.92; H, 7.06; Cl, 8.44; N, 6.04.

Optical rotation: [α]²⁰ _(D) -40.4° (c=1, methanol).

4.(-)-cis-8,9-Diethoxy-6-(4-methoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₅ H₃₀ N₂ O₄ ×1.25HCl×1.12H₂ O; MW: 485.9; m.p. 143≧148° C.; yield:76% of theory;

Elemental analysis: Calc.: C, 61.79; H, 6.97; Cl, 8.18; N, 5.76. Found:C, 61.88; H, 6.88; Cl, 8.34; N, 5.70.

Optical rotation: [α]²⁰ _(D) -50.2° (c=1 methanol).

5.(-)-cis-8,9-Diethoxy-6-(4-isopropoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₇ H₃₄ N₂ O₄ ×1.1HCl×0.83H₂ O; MW: 505.64; m.p. 205-209° C., fromabout 165° C. slow agglutination; yield: 69% of theory;

Elemental analysis: Calc.: C, 64.17; H, 7.33; Cl, 7.72; N, 5.65. Found:C, 64.29; H, 7.37; Cl, 7.60; N, 5.65.

Optical rotation: [α]²⁰ _(D) -47.1° (c=1, methanol).

6.(-)-cis-6-(4-Aminocarbonylphenyl)-8,9-dimethoxyphenyl-2-methyl-1,2,3,4,4a10b-hexahydrobenzo[c][1,6]naphthyridine

The title compound from Example 1 is allowed to stand at RT for 48 h ina 1+1 vol. mixture of methanol and conc. ammonia solution. Afterconcentrating completely, the solid residue is recrystallized in amixture of 1 part by volume of methanol and 10 parts by volume ofdiethyl ether. 51% of theory of the title compound of m.p. 229-232° C.is obtained.

EF: C₂₂ H₂₅ N₃ O₃ ; MW: 379.46;

Elemental analysis: Calc.: C, 69.64; H, 6.64; N, 11.07. Found: C, 69.41;H, 6.54; N, 11.00.

Optical rotation: [α]²⁰ D=-104.7° (c=1, methanol).

7.(-)-cis-6-(4-Carboxyphenyl)-8,9-dimethoxyphenyl-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine

The ester group of the title compound from Example 1 is hydrolyzed at RTin a mixture of methanol and 2N sodium hydroxide solution. Afterhydrolysis is complete, the mixture is neutralized by addition of anappropriate amount of hydrochloric acid and the suspension obtained islargely concentrated (removal of the methanol). The solid residue issuspended using water and filtered off with suction. After thoroughwashing with water, the filter residue consists of the title compound,which after drying has an m.p. of 237-240° C.

EF: C₂₂ H₂₄ N₂ O₄ ×0.5H₂ O; MW: 389.46; yield: 80% of theory;

Elemental analysis: Calc.: C, 67.85; H, 6.47; N, 7.19. Found: C, 68.05;H, 6.62; N, 7.24.

Analogously to Example 7, the following 2 title compounds are obtainedby hydrolysis of the corresponding esters described above:

8.(-)-cis-6-(3-Carboxyphenyl)-8,9-dimethoxyphenyl-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine

EF: C₂₂ H₂₄ N₂ O₄ ; MW: 380.45; yield: 76% of theory; m.p. from about168° slow agglutination, from about 230° C. decomposition.

9.(-)-cis-6-(4-Carboxyphenyl)-8,9-diethoxyphenyl-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine

EF: C₂₄ H₂₈ N₂ O₄ ; MW: 408.50; yield: 88% of theory; m.p.>240° C.(decomposition).

The following title compounds are obtained analogously to Example 1 whenthe piperidines appropriately substituted in the 4-position are employedas starting compounds for the cyclocondensation. These are obtained inthe manner described below for the starting compound A when appropriateterephthalic acid monoamides are employed.

10.(-)-cis-8,9-Diethoxy-6-(4-dimethylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₆ H₃₃ N₃ O₃ ×HCl×H₂ O; MW: 490.05; m.p.: 142-150° C. (solid foamedproduct); yield: 46% of theory;

Elemental analysis: Calc.: C, 63.73; H, 7.40; Cl, 7.23; N, 8.57. Found:C, 64.08; H, 7.32; Cl, 7.48; N, 8.31.

Optical rotation: [α]²⁰ _(D) -28.9° (c=1, methanol).

11.(-)-cis-8,9-Diethoxy-6-(4-diisopropylaminocarbonylphenyl-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₃₀ H₄₁ N₃ O₃ ×HCl×1.4H₂ O; MW: 553.37; m.p.: 164-180° C. (unsharprange); yield: 30% of theory;

Elemental analysis: Calc.: C, 65.12; H, 8.16; Cl, 641; N, 7.59. Found:C, 64.85; H, 8.29; Cl, 6.50; N, 7.66.

Optical rotation: [α]²⁰ _(D) -42.0° (c=1, methanol).

12.(-)-cis-8,9-Dimethoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₈ H₃₇ N₃ O₃ ×HCl×2.4H₂ O; MW: 542.32; m.p.: 175-185° C. (unsharprange); yield: 24% of theory;

Elemental analysis: Calc.: C, 62.01; H, 7.77; Cl, 6.54; N, 7.75. Found:C, 61.88; H, 7.81; Cl, 6.68; N, 7.73.

Optical rotation: [α]²⁰ _(D) -60.6° (c=1, methanol).

13.(-)-cis-8,9-Dimethoxy-6-(4-dimethylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₄ H₂₉ N₃ O₃ ×HCl×0.6H₂ O; MW: 454.79; m.p.: 226-228° C.(decomposition); yield: 21% of theory;

Elemental analysis: Calc.: C, 63.38; H, 6.92; Cl, 7.80; N, 9.24. Found:C, 63.10; H, 7.13; Cl, 8.12; N, 9.14.

Optical rotation: [α]²⁰ _(D) -58.0.° (c=1, methanol).

14.(+)-cis-8,9-Diethoxy-2-methyl-6-[4-(4-morpholinocarbonyl)phenyl]-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₈ H₃₅ N₃ O₄ ×1.25HCl×H₂ O; MW: 541.20; m.p.: 165-170° C. (unsharprange); yield: 45% of theory;

Elemental analysis: Calc.: C, 62.14; H, 7.12; Cl, 8.19; N, 7.76. Found:C, 62.30; H, 7.21; Cl, 7.96; N, 7.35.

Optical rotation: [α]²⁰ D=+12.4° (c=1, methanol).

15. (+)-cis-8,9-Diethoxy-6-(4-dicyclohexylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine hydrochloride

EF: C₃₆ H₄₉ N₃ O₃ ×1.2HCl×1.4H₂ O; MW: 640.78; m.p.: 195-202° C.(unsharp range); yield: 65% of theory;

Elemental analysis: Calc.: C, 67.48; H, 8.34; Cl, 6.64; N, 6.56. Found:C, 67.53; H, 8.16; Cl, 6.62; N, 6.71.

Optical rotation: [α]²⁰ D=+24.2° (c=1, methanol).

16.(+)-cis-8,9-Diethoxy-6-(4-N-cyclohexyl-N-isopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₃₃ H₄₅ N₃ O₃ ×1.25HCl×1H₂ O; MW: 595.33; m.p.: 163-195° C. (unsharprange); yield: 57% of theory;

Elemental analysis: Calc.: C, 66.58; H, 8.17; Cl, 7.44; N, 7.06. Found:C, 66.71; H, 8.04; Cl, 7.42; N, 7.25.

Optical rotation: [α]²⁰ D=+21.6° (c=1, methanol).

17.(+)-cis-8,9-Diethoxy-6-(4-dibutylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₃₂ H₄₅ N₃ O₃ ×2HCl×0.9H₂ O; MW: 608.88; m.p.: 144-162° C. (unsharprange; decomposition); yield: 62% of theory;

Elemental analysis: Calc.: C, 63.13; H, 8.08; Cl, 11.65; N, 6.90. Found:C, 63.29; H, 8.18; Cl, 11.61; N, 6.80.

Optical rotation: [α]²⁰ D=+191.7° (c=1, methanol).

18.(-)-cis-8,9-Diethoxy-6-[4-(hexahydroazepin-1-yl-carbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₃₀ H₃₉ N₃ O₃ ×1.2HCl×0.6H₂ O; MW: 544.23; m.p.: 138-154° C.(unsharp range); yield: 58% of theory;

Elemental analysis: Calc.: C, 66.21; H, 7.66; Cl, 7.81; N, 7.72. Found:C, 66.17; H, 7.70; Cl, 7.80; N, 7.71.

Optical rotation: [α]²⁰ _(D) -11.5° (c=1, methanol).

19.(-)-cis-9-Ethoxy-8-methoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₉ H₃₉ N₃ O₃ ×HCl×0.6H₂ O; MW: 524.92; m.p.: 175-179° C. (unsharp);yield: 67% of theory;

Elemental analysis: Calc.: C, 66.36; H, 7.91; Cl, 6.75; N, 8.01. Found:C, 66.28; H, 7.99; Cl, 6.87; N, 7.97.

Optical rotation: [α]²⁰ _(D) -42.7° (c=1,methanol).

20.(-)-cis-8-Ethoxy-9-methoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₉ H₃₉ N₃ O₃ ×1.03HCl×0.94H₂ O; MW: 532.16; m.p.: 176-179° C.(unsharp); yield: 43% of theory;

Elemental analysis: Calc.: C, 65.49; H, 7.94; Cl, 6.87; N, 7.90. Found:C, 65.43; H, 7.71; Cl, 6.86; N, 7.99.

Optical rotation: [α]²⁰ _(D) -48.0° (c=1, methanol).

21.(-)-cis-9-Ethoxy-8-methoxy-6-(4-methoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₄ H₂₈ N₂ O₄ ×1.05HCl×1.27 H₂ O; MW:; m.p.: 150-160° C. (sintering,unsharp range); yield: 89% of theory;

Elemental analysis: Calc.: C, 61.37; H, 6.78; Cl, 7.92; N, 5.96. Found:C, 61.39; H, 6.77; Cl, 7.93; N, 5.94.

Optical rotation: [α]²⁰ _(D) -84.3° (c=1, methanol).

22.(-)-cis-9-Ethoxy-8-methoxy-6-(3-methoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₄ H₂₈ N₂ O₄ ×HCl×0.66H₂ O; MW: 456.82; m.p.: sintering from about140° C., slow melting with decomposition up to about 150° C.; yield: 88%of theory;

Elemental analysis: Calc.: C, 63.11; H, 6.69; Cl, 7.76; N, 6.13. Found:C, 62.98; H, 6.78; Cl, 7.89; N, 6.07.

Optical rotation: [α]²⁰ _(D) -143.1° (c=1, methanol).

23.(-)-cis-9-Ethoxy-8-methoxy-6-(4-dibutylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₃₁ H₄₃ N₃ O₃ ×1.1HCl×1.17H₂ O; MW: 566.82; m.p.: 104-112° C. (solidfoamed product, slow deliquescence); yield: 60% of theory;

Elemental analysis: Calc.: C, 65.68; H, 8.26; Cl, 6.88; N, 7.41. Found:C, 65.80; H, 8.09; Cl, 6.97; N, 7.49.

Optical rotation: [α]²⁰ _(D) -16.2° (c=1, methanol).

24.(-)-cis-9-Ethoxy-8-methoxy-6-[4-(hexahydroazepin-1-yl-carbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine

EF: C₂₉ H₃₇ N₃ O₃ ; MW: 475.65; m.p.: 135-142° C. (unsharp range,sintering from about 125° C.); yield: 66% of theory;

Elemental analysis: Calc.: C, 73.23; H, 7.84; N, 8.83. Found: C, 73.02;H, 8.08; N, 8.67.

Optical rotation: [α]²⁰ _(D) -72.5° (c=1, methanol).

25.(-)-cis-9-Ethoxy-8-methoxy-6-[4-(piperidin-1-yl-carbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride

EF: C₂₈ H₂₅ N₃ O₃ ×0.4H₂ O; MW: 468.82; m.p.: 79-82° C. (unsharp range);yield: 43% of theory;

Elemental analysis: Calc.: C, 71.70; H, 7.70; N, 8.96. Found: C, 71.78;H, 7.71; N, 8.97.

Optical rotation: [α]²⁰ _(D) -77.2° (c=1, methanol).

Analogously to Example 7, the following 2 title compounds are obtainedby hydrolysis of the corresponding esters described above.

26.(-)-cis-6-(4-carboxyphenyl)-9-ethoxy-8-methoxyphenyl-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine

EF: C₂₃ H₂₆ N₂ O₄ ×1.1H₂ O; MW: 414.29; m.p.: 240-242° C. (decompositionwith red coloration); yield: 91% of theory;

Elemental analysis: Calc.: C, 66.68; H, 6.86; N, 6.76. Found: C, 66.81;H, 6.75; N, 6.70.

Optical rotation: [α]²⁰ _(D) -109.7° (c=1, methanol+1.0 equivalent of0.1N NaOH).

27.(-)-cis-6-(3-Carboxyphenyl)-9-ethoxy-8-methoxyphenyl-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine

EF: C₂₃ H₂₆ N₂ O₄ ×0.54H₂ O; MW: 404.17; m.p.: 158-170° C.(decomposition); yield: 83% of theory;

Elemental analysis: Calc.: C, 68.36; H, 6.75; N, 6.93. Found: C, 68.25;H, 6.86; N, 6.96.

Optical rotation: [α]²⁰ _(D) -150.7° (c=1, methanol+1.0 equivalent of0.1N NaOH).

STARTING COMPOUNDS

A. (-)-cis-Terephthalic acidN-[3-(3,4-dimethoxyphenyl)-1-methylpiperidin-4-yl]amide monomethyl ester

A solution of monomethyl terephthaloyl chloride (prepared from 2.2 g ofmonomethyl terephthalate and thionyl chloride) in 5 ml ofdichloromethane is added dropwise at RT in the course of 10 min. to asolution of 3 g of(-)-cis-4-amino-3-(3,4-dimethoxyphenyl)-1-methylpiperidine (prepared byextraction of the free base with dichloromethane after treatment of thecorresponding dihydrochloride ([α]²⁰ D=-57.1°, c=1, methanol) withdilute sodium hydroxide solution) in 10 ml of dichloromethane and 1.9 mlof triethylamine. After stirring for about 2 h, the mixture is extractedwith about 50 ml of saturated sodium hydrogencarbonate solution, and theorganic phase is washed a further two times with 50 ml of water eachtime and dried over sodium sulfate. The viscous residue remaining afterconcentration is purified by column chromatography. The main productfraction concentrated in vacuo affords a solid foaming residue which isrecrystalized in a mixture of methanol and diethyl ether (about 1+1vol.). 2.3 g of the title compound having the m.p. 151-152° C. areobtained; yield: 47% of theory; EF: C₂₃ H₂₈ N₂ O₅ ; MW: 412.48.

Elemental analysis: Calc. C, 66.97; H, 6.84; N, 6.79. Found C, 66.82; H,6.97; N, 6.97.

Optical rotation: [α]²² _(D) -74.9° (c=1, methanol).

Starting from the corresponding starting compounds, the following titlecompounds are obtained analogously to the procedure according to ExampleA:

B. (-)-cis-Isophthalic acidN-[3-(3,4dimethoxyphenyl)-1-methylpiperidin-4-yl]amide monomethyl ester

EF: C₂₃ H₂₈ N₂ O₅ ; MW: 412.49; yield: 63% of theory; m.p.: 122-123° C.;

Optical rotation: [α]²⁰ _(D) -30.6° (c=1, methanol).

C. (-)-cis-Terephthalic acidN-[3-(3,4-dimethoxyphenyl)-1-methylpiperidin-4-yl]amide monoisopropylester

EF: C₂₅ H₃₂ N₂ O₅ ; MW: 440.54; yield: 60% of theory; m.p.: 136-142° C.(unsharp);

Optical rotation: [α]²⁰ _(D) -48.2° (c=1, methanol).

D. (-)-cis-Terephthalic acidN-[3-(3,4-diethoxyphenyl)-1-methylpiperidin-4-yl]amide monomethyl ester

EF: C₂₅ H₃₂ N₂ O₅ ; MW: 440.54; yield: 55% of theory; m.p.: 169-173° C.(unsharp);

Optical rotation: [α]²⁰ _(D) -66.4° (c=1, methanol).

The title compound is obtained by the process described in Example Awhen (-)-cis-4-amino-3(3,4-diethoxyphenyl)-1-methylpiperidine having theoptical rotation [α]²⁰ _(D) -35.1°(dihydrochloride, solid foamed crudeproduct, c=1, methanol) is employed as the amine component.

E. (-)-cis-Terephthalic acidN-[3-(3,4-diethoxyphenyl)-1-methylpiperidin-4-yl]amide monoisopropylester

EF: C₂₇ H₃₆ N₂ O; MW: 468.6; yield: 63% of theory; m.p.: 119-126° C.(unsharp);

Optical rotation: [α]²⁰ _(D) -51.5° (c=1, methanol).

F. (-)-cis-4-Amino-3-(3,4-diethoxyphenyl)-1-methylpiperidinedihydrochloride

The title compound is obtained analogously to the process described inDE 42 17 401 when the corresponding 3,4-diethoxy compounds are employedin the examples described there.

EF: C₁₆ H₂₆ N₂ O₂ ×2HCl; MW: 351.32; obtained as a solid foamed crudeproduct; m.p.: shrinkage and slow deliquescence from about 120° C.,unsharp melting range up to about 150° C.;

Optical rotation: [α]²⁰ _(D) -35.1° (c=1, methanol).

G.(-)-cis-N-[3-(3,4-Diethoxyphenyl)-1-methylpiperidin-4-yl]-4-(morpholine-4-carbonyl)benzamide

EF: C₂₈ H₃₇ N₃ O₅ ; MW: 495.6; yield: 71% of theory: m.p.: 178-179° C.;

Optical rotation: [α]²⁰ _(D) -57.3 ° (c=1, methanol).

H. (-)-cis-Terephthalic acidN,N-dibutyl-N'-[3-(3,4-diethoxyphenyl)-1-methylpiperidin-4-yl]-diamide

EF: C₃₂ H₄₇ N₃ O₄ ×0.25H₂ O; MW: 537.75; yield: 76% of theory; m.p.:115-120° C.;

Optical rotation: [α]²⁰ _(D) -57.0° (c=1, methanol).

I. (-)-cis-Terephthalic acidN-cyclohexyl-N'-[3-(3,4-diethoxyphenyl)-1-methylpiperidin-4-yl]-N-isopropyldiamide

EF: C₃₃ H₄₇ N₃ O₄ ; MW: 549.76; yield: 66% of theory; m.p.: 59-64° C.(unsharp range, solidified foam);

Optical rotation: [α]²⁰ _(D) -39.9° (c=1, methanol).

J. (-)-cis-Terephthalic acidN,N-diisopropyl-N'-[3-(3-ethoxy-4-methoxyphenyl)-1-methylpiperidin-4-yl]diamide

CH: C₂₉ H₄₁ N₃ O₄ ; MW: 495.67; yield: 91% of theory; m.p.: 75-82° C.(unsharp range, solidified foam);

Optical rotation: [α]²⁰ _(D) -60.1° (c=1, methanol).

K. (-)-cis-Terephthalic acidN,N-diisopropyl-N'-[3-(4-ethoxy-3-methoxyphenyl)-1-methylpiperidin-4-yl]diamide

EF: C₂₉ H₄₁ N₃ O₄ ; MW: 495.67; yield: 89% of theory; m.p.: 72-80° C.(unsharp range, solidified foam).

L. (-)-cis-Terephthalic acidN,N-dibutyl-N'-[3-(3-ethoxy-4-methoxyphenyl)-1-methylpiperidin-4-yl]diamide

EF: C₃₁ H₄₅ N₃ O₄ ; MW: 523.73; yield: 90% of theory; m.p.: 98-102° C.

M.(-)-cis-4-Hexahydroazepine-1-carbonyl)-N-[3-(3-ethoxy-4-methoxyphenyl)-1-piperidin-4-yl]benzamide

EF: C₂₉ H₃₉ N₃ O₄ ; MW: 493.66; yield: 98% of theory; m.p.: 63-66° C.(unsharp range, solidified foam).

The following compounds are obtained analogously to the processdescribed in DE 42 17 401 when the corresponding 4-ethoxy-3-methoxy or3-ethoxy-4-methoxy compounds are employed in the examples describedthere:

N. (-)-cis-4-Amino-3-(4-ethoxy-3-methoxyphenyl)-1-methylpiperidinedihydrochloride

EF: C₁₅ H₂₄ N₂ O₂ ×2HCl×0.32H₂ O; MW: 343.06; m.p.: 241-243° C.;

Optical rotation: [α]²⁰ _(D) -59.5° (c=1, methanol).

O. (-)-cis-4-Amino-3-(3-ethoxy-4-methoxyphenyl)-1-methylpiperidinedihydrochloride

EF: C₁₅ H₂₄ N₂ O₂ ×2HCl×0.96H₂ O; MW: 354.52; m.p.: 252-254° C.;

Optical rotation: [α]²⁰ _(D) -65.5° (c=1, methanol).

COMMERCIAL UTILITY

The compounds according to the invention have valuable pharmacologicalproperties which make them commercially utilizable. As selectiveinhibitors of type 3 and 4 of cyclic nucleotide phosphodiesterase (PDE3,PDE4), they are suitable on the one hand as bronchial therapeutics (forthe treatment of airway obstructions on account of their dilating andcilium-stimulating action but also on account of their respiratoryrate--and respiratory drive--increasing action), but on the other handespecially for the treatment of disorders of inflammatory nature, e.g.of the airways (asthma prophylaxis), of the skin, of the intestine, ofthe eyes and of the joints, which are mediated by mediators such asinterferons, members of the tumor necrosis factor family, interleukins,chemokines, colony-stimulating factors, growth factors, lipid mediators(e.g., inter alia, PAF, platelet-activating factor), bacterial factors(e.g. LPS), immunoglobulins, oxygen free radicals and related freeradicals (e.g. nitrogen monoxide NO), biogenic amines (e.g. histamine,serotonin), kinins (e.g. bradykinin), neurogenic mediators (such assubstance P, neurokinin), proteins such as, for example, granularcontents of leukocytes (inter alia cationic proteins of eosinophils) andadherent proteins (e.g. integrins). The compounds according to theinvention have smooth muscle-relaxant action, e.g. in the region of thebronchial system, of the blood circulation, and of the efferent urinarypassages. Furthermore they have a cilium-frequency increasing action,e.g. in the bronchial system.

In this context, the compounds according to the invention aredistinguished by low toxicity, good human acceptance, good enteralabsorption and high bioavailability, great therapeutic breadth, theabsence of significant side effects and good water solubility.

On account of their PDE-inhibiting properties, the compounds accordingto the invention can be employed as therapeutics in human and veterinarymedicine, where they can be used, for example, for the treatment andprophylaxis of the following diseases: acute and chronic (in particularinflammatory and allergen-induced) airway disorders of various origin(bronchitis, allergic bronchitis, bronchial asthma); disorders with areduction of the cilium activity or with increased demands on the ciliarclearance (bronchitis, mucoviscidose); dermatoses (especially ofproliferative, inflammatory and allergic type) such as, for example,psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema,seborrheic eczema, lichen simplex, sunburn, pruritis in the anogenitalarea, alopecia areata, hypertrophic scars, discoid lupus erythematosus,follicular and widespread pyodermias, endogenous and exogenous acne,acne rosacea and other proliferative, inflammatory and allergic skindisorders; disorders which are based on excessive release of TNF andleukotrienes, i.e., for example, disorders of the arthritis type(rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and otherarthritic conditions), systemic lupus erythematosus, disorders of theimmune system (AIDS), including AlDS-related encephalopathies,autoimmune disorders such as diabetes mellitus (Type I autoimmunediabetes), multiple sclerosis and of the type virus-, bacteria- orparasite-induced demyelinization diseases, cerebral malaria or Lyme'sdisease, shock symptoms [septic shock, endotoxin shock, Gram-negativesepsis, toxic shock syndrome and ARDS (adult respiratory distresssyndrome)] and also generalized inflammations in the gastrointestinalregion (Crohn's disease and ulcerative colitis); disorders which arebased on allergic and/or chronic, faulty immunological reactions in theregion of the upper airways (pharynx, nose) and of the adjacent regions(paranasal sinuses, eyes), such as, for example, allergicrhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitisand also nasal polyps: and also disorders of the central nervous systemsuch as memory disorders and Alzheimer's disease, candidiasis,leishmaniases and leprosy.

On account of their vasorelaxant activity, the compounds according tothe invention can also be used for the treatment of high blood pressuredisorders of various origin such as, for example, pulmonary high bloodpressure and the concomitant symptoms associated therewith, for thetreatment of erectile dysfunction or colics of the kidneys and theureters in connection with kidney stones.

On account of their cAMP-increasing action, however, they can also beused for disorders of the heart which can be treated by PDE inhibitors,such as, for example, cardiac insufficiency, and also asanti-thrombotic, platelet aggregation-inhibiting substances.

The invention further relates to a method for the treatment of mammalsincluding humans who are suffering from one of the abovementioneddiseases. The method comprises administering a therapeutically effectiveand pharmacologically tolerable amount of one or more of the compoundsaccording to the invention to the sick mammal.

The invention further relates to the compounds according to theinvention for use in the treatment and/or prophylaxis of the diseasesmentioned.

The invention also relates to the use of the compounds according to theinvention for the production of medicaments which are employed for thetreatment and/or prophylaxis of the diseases mentioned.

The invention furthermore relates to medicaments for the treatmentand/or prophylaxis of the diseases mentioned and which contain one ormore of the compounds according to the invention.

Advantageously, the substances according to the invention are alsosuitable for combination with other substances which bring aboutstimulation of cAMP, such as prostaglandins (PGE2, PGI2 andprostacyclin) and their derivatives, direct adenylate cyclasestimulators such as forskolin and related substances, or substancesindirectly stimulating adenylate cyclase, such as catecholamines andadrenergic receptor agonists, in particular beta mimetics. Incombination, on account of their cAMP degradation-inhibiting action,they in this case display a synergistic, superadditive activity. Thiscomes to bear, for example, in their use in combination with PGE2 forthe treatment of pulmonary hypertension.

The medicaments are prepared by methods known per se familiar to theperson skilled in the art. As medicaments, the compounds according tothe invention (=active compounds) are either employed as such, orpreferably in combination with suitable pharmaceutical auxiliaries, e.g.in the form of tablets, coated tablets, capsules, suppositories,patches, emulsions, suspensions, gels or solutions, the active compoundcontent advantageously being between 0.1 and 95%.

The person skilled in the art is familiar on the basis of his expertknowledge with the auxiliaries which are suitable for the desiredpharmaceutical formulations. Beside solvents, gel-forming agents,ointments bases and other active compound excipients, it is possible touse, for example, antioxidants, dispersants, emulsifiers, preservatives,solubilizers or permeation promoters.

For the treatment of disorders of the respiratory tract, the compoundsaccording to the invention are preferably also administered byinhalation. For this purpose, these are administered either directly asa powder (preferably in micronized form) or by atomization of solutionsor suspensions which contain them. With respect to the preparations andadministration forms, reference is made, for example, to the details inEuropean Patent 163 965.

For the treatment of dermatoses, the compounds according to theinvention are used in particular in the form of those medicaments whichare suitable for topical application. For the production of themedicaments, the compounds according to the invention (=activecompounds) are preferably mixed with suitable pharmaceutical auxiliariesand additionally processed to give suitable pharmaceutical formulations.Suitable pharmaceutical formulations which may be mentioned are, forexample, powders, emulsions, suspensions, sprays, oils, ointments, fattyointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by methods knownper se. The dosage of the active compounds takes place in the order ofmagnitude customary for PDE inhibitors. Thus topical application forms(such as, for example, ointments) for the treatment of dermatosescontain the active compounds in a concentration of, for example,0.1-99%. The dose for administration by inhalation is customarilybetween 0.01 and 10 mg per spray burst. The customary dose in the caseof systemic therapy (p.o. or i.v.) is between 0.1 and 200 mg peradministration.

BIOLOGICAL INVESTIGATIONS

In the investigation of PDE4 inhibition at the cellular level, theactivation of inflammatory cells has particular importance. An examplewhich may be mentioned is the FMLP(N-formylmethionylleucyl-phenylalanine)-induced superoxide production ofneutrophilic granulocytes, which can be measured as luminol-potentiatedchemoluminescence [McPhail L C, Strum S L, Leone P A and Sozzani S, Theneutrophil respiratory burst mechanism. In "Immunology Series" 1992, 57,47-76; ed. Coffey R G (Marcel Decker, Inc., New York-Basel-Hong Kong)].

Substances which inhibit chemoluminescence and cytokine secretion andthe secretion of inflammation-increasing mediators in inflammatorycells, in particular neutrophilic and eosinophilic granulocytes, arethose which inhibit PDE4. This isoenzyme of the phosphodiesterasefamilies is particularly represented in granulocytes. Its inhibitionleads to an increase in the intracellular cyclic AMP concentration andthus to the inhibition of cellular activation. PDE4 inhibition by thesubstances according to the invention is thus a central indicator of thesuppression of inflammatory processes. (Giembycz M A, Couldisoenzyme-selective phosphodiesterase inhibitors render bronchodilatorytherapy redundant in the treatment of bronchial asthma? BiochemPharmacol 1992, 43, 2041-2051; Torphy T J et al., Phosphodiesteraseinhibitors: new opportunities for treatment of asthma. Thorax 1991, 46,512-523; Schudt C et al., Zardaverine: a cyclic AMP PDE3/4 inhibitor. In"New Drugs for Asthma Therapy", 379-402, Birkhauser Verlag Basel 1991;Schudt C et al., influence of selective phosphodiesterase inhibitors onhuman neutrophil functions and levels of cAMP and Ca.Naunyn-Schmiedebergs Arch Pharmacol 1991, 344, 682-690; Nielson C P etal., Effects of selective phosphodiesterase inhibitors onpolymorphonuclear leukocytes respiratory burst. J Allergy Clin Immunol1990, 86, 801-808; Schade et al., The specific type 3 and 4phosphodiesterase inhibitor zardaverdne suppress formation of tumornecrosis factor by macrophages. European Journal of Pharmacology 1993,230, 9-14).

A. Methodology

1. Inhibition of PDE Isoenzymes

The PDE activity was determined according to Thompson et al. (1) withsome modifications (2). The test samples contained 40 mM tris HCl (pH7.4), 5 mM MgCl₂, 0.5 μM cAMP or cGMP, [³ H] cAMP or [³ H]cGMP (about50,000 cpm/sample), the PDE isoenzyme-specific additions described ingreater detail below, the indicated concentrations of inhibitor and analiquot of the enzyme solution in a total sample volume of 200 μl. Stocksolutions of the compounds to be investigated in DMSO were prepared inconcentrations such that the DMSO content in the test samples did notexceed 1% by volume--to avoid an effect on the PDE activity. Afterpreincubation at 37° C. for 5 minutes, the reaction was started byaddition of the substrate (cAMP or cGMP). The samples were incubated at37° C. for a further 15 min. The reaction was terminated by addition of50 μl of 0.2N HCl. After cooling on ice for 10 minutes and addition of25 μg of 5'-nucleotidase (snake venom from Crotalus atrox), the mixturewas again incubated at 37° C. for 10 min and the samples were thenapplied to QAE Sephadex A-25 columns. The columns were eluted with 2 mlof 30 mM ammonium formate (pH 6.0). The radioactivity of the eluate wasmeasured and corrected by the corresponding blank values. The proportionof hydrolyzed nucleotide in no case exceeded 20% of the originalsubstrate concentration.

PDE1 (Ca²⁺ /calmodulin-dependent) from bovine brain: the inhibition ofthis isoenzyme was investigated in the presence of Ca²⁺ (1 mM) andcalmodulin (100 nM) using cGMP as a substrate (3).

PDE2 (cGMP-stimulated) from rat hearts was purified chromatographically[Schudt et al. (4)] and investigated in the presence of cGMP (5 μM)using cAMP as a substrate.

PDE3 (cGMP-inhibited) and PDE5 (cGMP-specific) were investigated inhomogenates of human blood platelets [Schudt et al. (4)] using cAMP orcGMP as a substrate.

PDE4 (cAMP-specific) was investigated in the cytosol of humanpolymorphonuclear leukocytes (PMNL) [isolated from leukocyteconcentrates, see Schudt et al. (5)] using cAMP as a substrate. The PDE3inhibitor motapizone (1 μM) was used in order to suppress the PDE3activity emanating from contaminating blood platelets.

2. Inhibition of the Formation of Reactive Oxygen Species in Human PMNL

The formation of reactive oxygen species determined with the aid ofluminol-potentiated chemiluminescence (5) and the isolation of the PMNLfrom human blood (6) was carried out essentially as described in (5) and(6): equal-size portions (0.5 ml) of the cell suspension (10⁷ cells/ml)were preincubated at 37° C. for 5 min in the absence or presence of thecompounds to be investigated in a buffer solution comprising 140 mMNaCl, 5 mM KCl, 10 mM HEPES, 1 mM CaCl₂ /MgCl₂, 1 mg/ml of glucose,0.05% (w/v) BSA (bovine serum albumin), 10 μM luminol and 4 μMmicroperoxidase. Stock solutions of the compounds to be investigated inDMSO were prepared in concentrations such that the DMSO content in thetest samples did not exceed 0.1% by volume--to avoid an effect on PDEactivity. After preincubation, the test samples were transferred intothe measuring apparatus ["Multi-Biolumnat" LB 9505C from Berthold(Wildbad, Germany)] before stimulation with the receptor agonist FMLP(N-fornylmethionylleucyl phenylalanine, 100 nM). The chemiluminescencewas recorded continuously for 3 min; from this the AUC values werecalculated.

3. Statistics

The IC₅₀ values were determined from the concentration-inhibition curvesby nonlinear regression using the GraphPad InPlot™ program (GraphPadSoftware Inc., Philadelphia, U.S.A.).

4. References

(1) Thompson W. J. and Appleman M. M., Assay of cyclic nucleotidephosphodiesterase and resolution of multiple molecular forms of theenzyme; Adv. Cycl. Nucl. Res. 1979, 10, 69-92

(2) Bauer A. C. and Schwabe U., An improved assay of cyclic 3',5'-nucleotide phosphodiesterase with QAE Sephadex A-25;Naunyn-Schmiedeberg's Arch. Pharmacol. 1980, 311, 193-198

(3) Gietzen K, Sadorf I, and Bader H., A model for the regulation of thecalmodulin-dependent enzymes erythrocyte Ca²⁺ --transport ATPase andbrain phosphodiesterase by activators and inhibitors; Biochem. J. 1982,207, 541-548.

(4) Schudt C., Winder S., Muller B. and Ukena D., Zardaverine as aselective inhibitor of phosphodiesterase isoenzymes; Biochem. Pharmacol.1991, 42, 153-162

(5) Schudt C., Winder S., Forderkunz S., Hatzelmann A. and Ullrich V.,Influence of selective phosphodiesterase inhibitors on human neutrophilfunctions and levels of cAMP and Ca;

Naunyn-Schmiedeberg's Arch. Pharmacol. 1991, 344, 682-90

(6) Hatzelmann A. and Ullrich V., Regulation of 5-lipoxygenase activityby the glutathione status in human polymorphonuclear leukocytes; Eur. J.Biochem. 1987, 169, 175-184

B. Results

In Table 1 below, the inhibitory concentrations determined according toSection A1 [inhibitory concentrations as -log IC₅₀ (mol/l)] for thecompounds according to the invention are indicated for various PDEisoenzymes. The numbers of the compounds correspond to the numbers ofthe examples.

Table 1

    ______________________________________                                                log IC.sub.50, mol/l]                                                 Compound  PDE5      PDE4   PDE3   PDE2 PDE1                                   ______________________________________                                         3                  6.45   7.14                                                4        5.45      7.54   6.67   4.80 <4                                      5                  7.75   7.15                                               11                  7.85   7.23                                               16                  7.96   6.73                                               17                  7.94   6.38                                               18                  7.87   6.74                                               19                  8.18   7.56                                               21                  7.67   6.34                                               23                  8.56   6.64                                               24                  8.51   7.64                                               ______________________________________                                    

I claim:
 1. A compound of formula I ##STR6## in which R1 is1-4C-alkyl,R2 is hydroxyl, 1-4C-alkoxy, 3-7C-cycloalkoxy,3-7C-cycloalkylmethoxy or 1-4C-alkoxy which is completely orpredominantly substituted by fluorine, R3 is hydroxyl, 1-4C-alkoxy,3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 1-4C-alkoxy which iscompletely or predominantly substituted by fluorine,or in which R2 andR3 together are a 1-2C-alkylenedioxy group, R4 is a phenyl radical whichis substituted by R5 and R6, where R5 is hydrogen, hydroxyl, halogen,nitro, 1-4C-alkyl, trifluoromethyl or 1-4C-alkoxy, R6 is CO--R7 orCO--R8, where R7 is hydroxyl, 1-8C-alkoxy, 3-7C-cycloalkoxy or3-7C-cycloalkylmethoxy and R8 is N(R81)R82, where R81 and R82independently of one another are hydrogen, 1-7C-alkyl, 3-7C-cycloalkylor 3-7C-cycloalkylmethyl, or where R81 and R82, together with thenitrogen atom to which both are bonded, are a 1-pyrrolidinyl,1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,or a saltthereof.
 2. A compound of formula I according to claim 1, in whichR1 is1-4C-alkyl, R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxyor 1-2C-alkoxy which is completely or predominantly substituted byfluorine, R3 is 1-4C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or1-2C-alkoxy which is completely or predominantly substituted byfluorine, R4 is a phenyl radical which is substituted by R5 and R6,where R5 is hydrogen, hydroxyl, halogen, nitro, 1-4C-alkyl,trifluoromethyl or 1-4C-alkoxy, R6 is CO--R7 or CO--R8, where R7 ishydroxyl, 1-8C-alkoxy, 3-7C-cycloalkoxy or 3-7C-cycloalkylmethoxy and R8is N(R81)R82, where R81 and R82 independently of one another arehydrogen, 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl, or whereR81and R82, together with the nitrogen atom to which both are bonded,are a 1-piperidyl, 1-hexahydroazepinyl or 4-morpholinyl radical,or asalt thereof.
 3. A compound of formula I according to claim 1, inwhichR1 is methyl, R2 is 1-4C-alkoxy, 3-7C-cycloalkoxy or 1-2C-alkoxywhich is completely or predominantly substituted by fluorine, R3 is1-4C-alkoxy, 3-7C-cycloalkoxy or 1-2C-alkoxy which is completely orpredominantly substituted by fluorine, R4 is a phenyl radical which issubstituted by R5 and R6, where R5 is hydrogen, hydroxyl, 1-4C-alkyl or1-4C-alkoxy, R6 is CO--R7 or CO--R8, where R7 is hydroxyl, 1-8C-alkoxyor 3-7C-cycloalkoxy and R8 is N(R81)R82, where R81and R82 independentlyof one another are hydrogen, 1-7C-alkyl or 3-7C-cycloalkyl, or where R81and R82, together with the nitrogen atom to which both are bonded, are a1-piperidyl, 1-hexahydroazepinyl or4-morpholinyl radical,or a saltthereof.
 4. A compound of formula I according to claim 1, in whichR1 ismethyl, R2 is methoxy or ethoxy, R3 is methoxy or ethoxy, R4 is a phenylradical which is substituted by R5 and R6, where R5 is hydrogen, R6 isCO--R7 or CO--R8, where R7 is hydroxyl or 1-8C-alkoxy and R8 isN(R81)R82, where R81 and R82 independently of one another are hydrogenor 1-4C-alkyl or 5--7C-cycloalkyl, or where R81 and R82, together withthe nitrogen atom to which both are bonded, are a 1-piperidyl,1-hexahydroazepinyl or 4-morpholinyl radical,or a salt thereof.
 5. Acompound of formula I according to claim 1, in whichR1 is methyl, R2 isethoxy, R3 is methoxy or ethoxy, R4 is a phenyl radical which issubstituted by R5 and R6, where R5 is hydrogen, R6 is CO--R7 or CO--R8,where R7 is 1-4C-alkoxy and R8 is N(R81)R82, where-R81 and R82independently of one another are 1-4C-alkyl or 5-7C-cycloalkyl, or whereR81 and R82, together with the nitrogen atom to which both are bonded,are a 1-piperidyl or 1-hexahydroazepinyl radical,or a salt thereof.
 6. Acompound of formula I according to claim 1, in which the hydrogen atomsin positions 4a and 10 b are in the cis position relative to oneanother, or a salt thereof.
 7. A compound of formula I according toclaim 1, which in the positions 4a and 10b have the same absoluteconfiguration as the compound(-)-cis-4-amino-3-(3,4-dimethoxyphenyl)-1-methylpiperidinedihydrochloride having the optical rotation [α]²² _(D) -57.1 ° (c=1,methanol).
 8. A compound selected from the group consistingofcis-8,9-Diethoxy-6-(4-isopropoxycarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;cis-8,9-Diethoxy-6-(4-diisopropylaminocarbonylphenyl-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][-1,6]naphthyridine;cis-8,9-Diethoxy-6-(4-N-cyclohexyl-N-isopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;cis-8,9-Diethoxy-6-(4-dibutylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][-1,6]naphthyridine;cis-8,9-Diethoxy-6-[4-(hexahydroazepin-1-ylcarbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;cis-8,9-Diethoxy-6-[4-(piperidin-1-ylcarbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]-naphthyridine;cis-9-Ethoxy-8-methoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;cis-9-Ethoxy-8-methoxy-6-(4-dibutylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine:cis-9-Ethoxy-8-methoxy-6-[4-(hexahydroazepin-1-yl-carbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine;cis-9-Ethoxy-8-methoxy-6-[4-(piperidin-1-ylcarbonyl)phenyl]-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridineanda salt thereof.
 9. A medicament composition comprising a customarypharmaceutical auxiliary and/or excipient and an effective amount of acompound of formula I according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 10. In a method of producing a medicamentcomposition comprising a customary pharmaceutical auxiliary or excipientand an effective amount of active ingredient for treating an airwaydisorder or an amenable dermatosis, the improvement wherein the activeingredient is a compound of formula I according to claim 1 or apharmaceutically acceptable salt thereof.
 11. In a method for treatingan airway disorder or an amenable dermatosis which comprisesadministering an effective amount of active ingredient to a subject inneed of such treatment, the improvement wherein the active ingredient isa compound of formula I according to claim 1 or a pharmaceuticallyacceptable salt thereof.
 12. A compound of formula I according to claim5, in whichR1 is methyl, R2 is ethoxy, R3 is methoxy, R4 is a phenylradical which is substituted by R5 and R6, where R5 is hydrogen, R6 isCO--R8, where R8 is N(R81)R82 and R81 and R82 are isopropyl, or a saltthereof.
 13. The compound according to claim 7, which is(-)-cis-9-ethoxy-8-methoxy-6-(4-diisopropylaminocarbonylphenyl)-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridinehydrochloride.